HCN hyperpolarization-activated cation channels inhibit EPSPs by interactions with M-type K+ channels

Abstract

Voltage-gated channels influence processing of synaptic potentials in dendrites. George et al. report the hyperpolarization-activated cation current (Ih) exerts both direct depolarizing and net inhibitory hyperpolarizing effects on subthreshold excitatory postsynaptic potentials, as a function of synaptic strength. Interaction of Ih with an M-type potassium current (Im) underlies the inhibition. The processing of synaptic potentials by neuronal dendrites depends on both their passive cable properties and active voltage-gated channels, which can generate complex effects as a result of their nonlinear properties. We characterized the actions of HCN (hyperpolarization-activated cyclic nucleotide-gated cation) channels on dendritic processing of subthreshold excitatory postsynaptic potentials (EPSPs) in mouse CA1 hippocampal neurons. The HCN channels generated an excitatory inward current (Ih) that exerted a direct depolarizing effect on the peak voltage of weak EPSPs, but produced a paradoxical hyperpolarizing effect on the peak voltage of stronger, but still subthreshold, EPSPs. Using a combined modeling and experimental approach, we found that the inhibitory action of Ih was caused by its interaction with the delayed-rectifier M-type K+ current. In this manner, Ih can enhance spike firing in response to an EPSP when spike threshold is low and can inhibit firing when spike threshold is high.